EP1542768A1 - Use of cytokine synthesis inhibitors for the treatment of dry eye disorders - Google Patents

Use of cytokine synthesis inhibitors for the treatment of dry eye disorders

Info

Publication number
EP1542768A1
EP1542768A1 EP03770254A EP03770254A EP1542768A1 EP 1542768 A1 EP1542768 A1 EP 1542768A1 EP 03770254 A EP03770254 A EP 03770254A EP 03770254 A EP03770254 A EP 03770254A EP 1542768 A1 EP1542768 A1 EP 1542768A1
Authority
EP
European Patent Office
Prior art keywords
inhibitors
dry eye
eye
cytokine synthesis
kinase inhibitors
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03770254A
Other languages
German (de)
English (en)
French (fr)
Inventor
Daniel A. Gamache
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Inc
Original Assignee
Alcon Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alcon Inc filed Critical Alcon Inc
Publication of EP1542768A1 publication Critical patent/EP1542768A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention is directed to the treatment of dry eye disorders.
  • the present invention is directed to the use of certain cytokine synthesis inhibitors in the treatment of dry eye and other disorders requiring the wetting of the eye in mammals.
  • Dry eye also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren's disease and cicatricial emphigoid manifest dry eye complications.
  • Practitioners have taken several approaches to the treatment of dry eye.
  • One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day.
  • Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
  • Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils.
  • Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998).
  • phospholipid compositions for the treatment of dry eye are disclosed in U.S. Patent Nos. 4,131 ,651 (Shah et al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980 and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371 ,108 (Korb et al.) and 5,578,586 (Glonek et al.).
  • U.S. Patent No. 5,174,988 discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
  • U.S. Patent No. 4,818,537 discloses the use of a lubricating, Iiposome-based composition
  • U.S. Patent No. 5,800,807 discloses compositions containing glycerin and propylene glycol for treating dry eye.
  • U.S. Patent No. 5,041 ,434 discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye conditions in post-menopausal women
  • U.S. Patent No. 5,290,572 discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production
  • U.S. Patent No. 4,966,773 discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
  • the present invention is directed to methods for the treatment of dry eye and other disorders requiring the wetting of the eye, including symptoms of dry eye associated with refractive surgery such as LASIK surgery.
  • certain cytokine synthesis inhibitors are administered to a patient suffering from dry eye or other disorders requiring wetting of the eye.
  • the cytokine synthesis inhibitors are preferably administered topically to the eye.
  • Fig. 1 shows the inhibition of hyperosmolarity-induced cytokine production from human comeal epithelial cells in vitro by SP-600125 and dexamethasone.
  • inhibitors of cytokine synthesis by nonimmune resident ocular surface cells are administered to a patient suffering from dry eye.
  • the compounds suitable for use in the present invention inhibit the synthesis of pro-inflammatory cytokines in nonimmune resident ocular surface cells by interfering with specific effectors of signaling cascades in these cells.
  • Effectors of cytokine synthesis targeted for inhibition in the treatment of dry eye include mitogen-activated kinases (MAP kinase, p38 kinase), c-jun N- terminal kinase (JNK) and l-kappa kinase (IKK).
  • inhibitors of enzymes which convert precursors of the pro-inflammatory cytokines IL-1 ⁇ (ICE, IL-1 converting enzyme) and TNF ⁇ (TACE, TNF-alpha converting enzyme) to the active species or inhibit the translation of cytokine mRNA provide dry eye therapy.
  • Cytokines promote further synthesis of pro-inflammatory cytokines through activation of Janus family tyrosine kinase (JAK) and signal transducers and activators of transcription (STAT) and, therefore, inhibitors of JAKs and STATs provide treatment of dry eye.
  • Inhibitors of activator protein- 1 (AP-1) suppress cytokine synthesis in ocular surface cells and provide dry eye therapy.
  • ligands of retinoid X receptors are known to suppress cytokine synthesis in epithelial cells and are suitable for use in the present invention.
  • the classes of cytokine synthesis inhibitors identified above are known.
  • Inhibitors of MAP kinases include (5-(2-amino-4-pyrimidinyl)-4- (4-fluorophenyI)-1-(4-piperidinyl)imidazole) ["SB-220025"].
  • Inhibitors of JNK include anthra[1 ,9-cd]pyrazol-6(2H)-one ["SP-600125”].
  • Inhibitors of ICE include pralnacasan (HMR3480/VX-740).
  • TNF mRNA translation inhibitors include (D)Arginyl-(D)Norleucyl-(D)Norleucyl-(D)Arginyl-(D)Norleucyl-
  • NFkB inhibitors include 2-chloro-N-[3,5-di(trifluoromethyl)phenyl]-4- (trifluoromethyl)pyrimidine-5-carboxamide ["SP-100030"], and triflusal.
  • AP-1 inhibitors include SP-100030.
  • RXR agonists include bexarotene.
  • Preferred cytokine synthesis inhibitors for use in the present invention are JNK inhibitors and AP-1 inhibitors.
  • compositions comprising one or more of the specified cytokine synthesis inhibitors and a pharmaceutically acceptable carrier for topical ophthalmic administration or implantation into the conjunctival sac or anterior chamber of the eye is administered to a mammal in need thereof.
  • the compositions are formulated in accordance with methods known in the art for the particular route of administration desired.
  • compositions administered according to the present invention comprise a pharmaceutically effective amount of one or more of the specified cytokine synthesis inhibitors.
  • a pharmaceutically effective amount is one which is sufficient to reduce or eliminate signs or symptoms of dry eye or other disorders requiring the wetting of the eye.
  • the total amount of cytokine synthesis inhibitor will be about 0.001 to 1.0% (w/w).
  • the compositions administered according to the present invention will be formulated as solutions, suspensions and other dosage forms for topical administration.
  • compositions are generally preferred, based on ease of formulation, as well as a patient's ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes.
  • the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions.
  • Suspensions may be preferred for cytokine synthesis inhibitors which are sparingly soluble in water.
  • compositions administered according to the present invention may also include various other ingredients, including but not limited to surfactants, tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added.
  • the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150 - 450 mOsm, preferably 250 - 350 mOsm).
  • compositions formulated for the treatment of dry eye-type diseases and disorders may also comprise aqueous carriers designed to provide immediate, short-term relief of dry eye-type conditions.
  • aqueous carriers designed to provide immediate, short-term relief of dry eye-type conditions.
  • Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures of both.
  • phospholipid carrier and “artificial tears carrier” refer to aqueous compositions which: (i) comprise one or more phospholipids (in the case of phospholipid carriers) or other compounds, which lubricate, "wet,” approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration; (ii) are safe; and (iii) provide the appropriate delivery vehicle for the topical administration of an effective amount of one or more of the specified cytokine inhibitors.
  • artificial tears compositions useful as artificial tears carriers include, but are not limited to, commercial products, such as Tears Naturale®, Tears Naturale II®, Tears Naturale Free®, and Bion Tears® (Alcon Laboratories, Inc., Fort Worth, Texas).
  • phospholipid carrier formulations include those disclosed in U.S. Patent Nos.
  • Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol, hydroxypropyl methyl cellulose ("HPMC"), carboxy methylcellulose sodium, hydroxy propylcellulose (“HPC”), dextrans, such as, dextran 70; water soluble proteins, such as gelatin; and vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, such as, carbomer 934P, carbomer 941 , carbomer 940, carbomer 974P.
  • monomeric polyols such as, glycerol, propylene glycol, ethylene glycol
  • polymeric polyols such as, polyethylene glycol, hydroxypropyl methyl cellulose (“HPMC”), carboxy methylcellulose sodium, hydroxy propylcellulose (“HPC”)
  • viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.
  • the phospholipid carrier or artificial tears carrier compositions will exhibit a viscosity of 1 to 400 centipoises ("cps").
  • Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
  • compositions of the present invention are intended for administration to a human patient suffering from dry eye or symptoms of dry eye.
  • such compositions will be administered topically.
  • the doses used for the above described purposes will vary, but will be in an effective amount to eliminate or improve dry eye conditions.
  • 1-2 drops of such compositions will be administered from once to many times per day.
  • a representative eye drop formulation is provided in Example 1 below.
  • the above composition is prepared by the following method.
  • the batch quantities of boric acid, sodium chloride, disodium edetate, and polyquaternium-1 are weighed and dissolved by stirring in 90% of the batch quantity of purified water.
  • the pH is adjusted to 7.4 ⁇ 0.1 with NaOH and/or HCI.
  • the batch quantity of the cytokine synthesis inhibitor as a stock solution is measured and added.
  • Purified water is added to q.s. to 100%. The mixture is stirred for five minutes to homogenize and then filtered through a sterilizing filter membrane into a sterile recipient.
  • Example 2 Inhibition of Hyperosmolarity-induced Cytokine Production from Human Corneal Epithelial Cells in vitro.
  • the ocular tear film in dry eye is abnormally hyperosmolar, which is irritating to ocular surface cells.
  • Treatment of human conjunctival epithelial cells with a hypertonic media elicits the production of pro-inflammatory cytokines.
  • a selective JNK inhibitor, anthra[1 ,9-cd]pyrazol-6(2H)-one was evaluated for inhibition of hyperosmolarity-induced cytokine secretion from the transformed human corneal epithelial cell line, CEPI-17.
  • CEPI-17 cells were grown in complete isotonic Keratinocyte Growth Medium (iso KGM) and plated in 48-well plates in iso KGM without hydrocortisone (iso KGM-HC).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP03770254A 2002-09-20 2003-08-26 Use of cytokine synthesis inhibitors for the treatment of dry eye disorders Withdrawn EP1542768A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US41246302P 2002-09-20 2002-09-20
US412463P 2002-09-20
PCT/US2003/026689 WO2004026406A1 (en) 2002-09-20 2003-08-26 Use of cytokine synthesis inhibitors for the treatment of dry eye disorders

Publications (1)

Publication Number Publication Date
EP1542768A1 true EP1542768A1 (en) 2005-06-22

Family

ID=32030872

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03770254A Withdrawn EP1542768A1 (en) 2002-09-20 2003-08-26 Use of cytokine synthesis inhibitors for the treatment of dry eye disorders

Country Status (14)

Country Link
US (2) US7026296B2 (https=)
EP (1) EP1542768A1 (https=)
JP (1) JP2006502183A (https=)
KR (1) KR20050057175A (https=)
CN (1) CN1684738A (https=)
AR (1) AR041262A1 (https=)
AU (1) AU2003278727A1 (https=)
BR (1) BR0314603A (https=)
CA (1) CA2497977A1 (https=)
MX (1) MXPA05003063A (https=)
PL (1) PL374700A1 (https=)
TW (1) TW200404534A (https=)
WO (1) WO2004026406A1 (https=)
ZA (1) ZA200502119B (https=)

Families Citing this family (61)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040082509A1 (en) 1999-10-12 2004-04-29 Christophe Bonny Cell-permeable peptide inhibitors of the JNK signal transduction pathway
CA2497977A1 (en) * 2002-09-20 2004-04-01 Alcon, Inc. Use of cytokine synthesis inhibitors for the treatment of dry eye disorders
KR20050086676A (ko) * 2002-11-15 2005-08-30 상스타트 메디칼 코포레이션 간질성 방광염을 치료하는 세포 조절 펩티드
WO2004093878A1 (en) 2003-04-16 2004-11-04 Alcon, Inc. Use of fused pyridazine derivatives for treating dry eye disorders
AU2004287875B2 (en) 2003-11-05 2011-06-02 Bausch + Lomb Ireland Limited Modulators of cellular adhesion
AU2004294343A1 (en) * 2003-12-01 2005-06-16 Vertex Pharmaceuticals Incorporated Treating infectious diseases using ICE inhibitors
US7803824B2 (en) * 2004-10-29 2010-09-28 Alcon, Inc. Use of inhibitors of Jun N-terminal kinases to treat glaucoma
US20060094753A1 (en) * 2004-10-29 2006-05-04 Alcon, Inc. Use of inhibitors of Jun N-terminal kinases for the treatment of glaucomatous retinopathy and ocular diseases
DK2444079T3 (en) 2005-05-17 2017-01-30 Sarcode Bioscience Inc Compositions and Methods for the Treatment of Eye Diseases
WO2006133426A2 (en) 2005-06-08 2006-12-14 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
US20070203161A1 (en) 2006-02-24 2007-08-30 Rigel Pharmaceuticals, Inc. Compositions and methods for inhibition of the jak pathway
KR20080033939A (ko) * 2005-06-17 2008-04-17 리지너크스 바이오 파마소티컬스, 인코포레이티드 동결 건조된 형태이거나, 또는 동결 건조될 수 있는 형태인엘케이케이티이티 및/또는 엘케이케이티엔티 펩티드조성물들
WO2007031098A1 (en) * 2005-09-12 2007-03-22 Xigen S.A. Cell-permeable peptide inhibitors of the jnk signal transduction pathway
CN1939534B (zh) * 2005-09-27 2010-12-01 长春金赛药业股份有限公司 含有人生长激素或人粒细胞巨噬细胞刺激因子的用于治疗损伤和溃疡的外用制剂
JP2007133001A (ja) * 2005-11-08 2007-05-31 Seed Co Ltd コンタクトレンズ用ケア用剤
EP2455382B1 (en) 2005-12-13 2016-10-26 Incyte Holdings Corporation Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors
US7745461B1 (en) 2006-02-27 2010-06-29 Alcon Research, Ltd. Method of treating dry eye disorders
EP2074138A4 (en) * 2006-09-19 2009-12-30 Phylogica Ltd NEUROPROTECTIVE PEPTIDE AP-1 SIGNALING INHIBITORS AND USES THEREOF
EP3070090B1 (en) 2007-06-13 2018-12-12 Incyte Holdings Corporation Use of salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h- pyrazol-1-yl)-3- cyclopentylpropanenitrile
ES2630406T3 (es) 2007-10-19 2017-08-21 Sarcode Bioscience Inc. Composición y procedimientos para el tratamiento de la retinopatía diabética
US8080562B2 (en) 2008-04-15 2011-12-20 Sarcode Bioscience Inc. Crystalline pharmaceutical and methods of preparation and use thereof
WO2009143865A1 (en) 2008-05-30 2009-12-03 Xigen S.A. Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases
WO2009143864A1 (en) * 2008-05-30 2009-12-03 Xigen S.A. Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of chronic or non-chronic inflammatory digestive diseases
CL2009001884A1 (es) * 2008-10-02 2010-05-14 Incyte Holdings Corp Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco.
WO2010072228A1 (en) 2008-12-22 2010-07-01 Xigen S.A. Novel transporter constructs and transporter cargo conjugate molecules
JP5775070B2 (ja) 2009-05-22 2015-09-09 インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ ヤヌスキナーゼ阻害剤としてのピラゾール−４−イル−ピロロ［２，３−ｄ］ピリミジンおよびピロール−３−イル−ピロロ［２，３−ｄ］ピリミジンのＮ−（ヘテロ）アリール−ピロリジン誘導体
SG176111A1 (en) 2009-05-22 2011-12-29 Incyte Corp 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors
CN102470135A (zh) * 2009-07-28 2012-05-23 里格尔药品股份有限公司 抑制jak途径的组合物和方法
AR078012A1 (es) 2009-09-01 2011-10-05 Incyte Corp Derivados heterociclicos de las pirazol-4-il- pirrolo (2,3-d) pirimidinas como inhibidores de la quinasa janus
US8378105B2 (en) 2009-10-21 2013-02-19 Sarcode Bioscience Inc. Crystalline pharmaceutical and methods of preparation and use thereof
PT3354652T (pt) 2010-03-10 2020-07-20 Incyte Holdings Corp Derivados de piperidin-4-ilazetidina como inibidores de jak1
RS54824B1 (sr) 2010-05-21 2016-10-31 Incyte Holdings Corp Topikalna formulacija za inhibiciju jak-a
WO2011160653A1 (en) 2010-06-21 2011-12-29 Xigen S.A. Novel jnk inhibitor molecules
AU2010362444B2 (en) 2010-10-14 2015-08-06 Xigen Inflammation Ltd. Use of cell-permeable peptide inhibitors of the JNK signal transduction pathway for the treatment of chronic or non-chronic inflammatory eye diseases
CA2818542A1 (en) 2010-11-19 2012-05-24 Incyte Corporation Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as jak inhibitors
WO2012068440A1 (en) 2010-11-19 2012-05-24 Incyte Corporation Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors
MY165963A (en) 2011-06-20 2018-05-18 Incyte Holdings Corp Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors
TW201313721A (zh) 2011-08-18 2013-04-01 Incyte Corp 作為ｊａｋ抑制劑之環己基氮雜環丁烷衍生物
UA111854C2 (uk) 2011-09-07 2016-06-24 Інсайт Холдінгс Корпорейшн Способи і проміжні сполуки для отримання інгібіторів jak
MX2014006399A (es) * 2011-11-30 2015-04-10 Xigen Inflammation Ltd Uso de inhibidores de peptidos con celulas permeables de la via para transduccion de señal de jnk para el tratamiento de la queratoconjuntivitis seca.
WO2013091670A1 (en) 2011-12-21 2013-06-27 Xigen S.A. Novel jnk inhibitor molecules for treatment of various diseases
TW201406761A (zh) 2012-05-18 2014-02-16 Incyte Corp 做爲ｊａｋ抑制劑之哌啶基環丁基取代之吡咯并吡啶及吡咯并嘧啶衍生物
CA2879982C (en) 2012-07-25 2020-09-01 Sarcode Bioscience Inc. Lfa-1 inhibitor and polymorph thereof
CN113384546A (zh) 2012-11-15 2021-09-14 因赛特公司 鲁索利替尼的缓释剂型
WO2014138168A1 (en) 2013-03-06 2014-09-12 Incyte Corporation Processes and intermediates for making a jak inhibitor
WO2015197097A1 (en) 2014-06-26 2015-12-30 Xigen Inflammation Ltd. New use for jnk inhibitor molecules for treatment of various diseases
ES2870085T3 (es) 2013-06-26 2021-10-26 Xigen Inflammation Ltd Inhibidores peptídicos permeables a células de la ruta de transducción de señales de JNK para el tratamiento de la cistitis
WO2014206427A1 (en) 2013-06-26 2014-12-31 Xigen Inflammation Ltd. New use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases
SG10201801069QA (en) 2013-08-07 2018-03-28 Incyte Corp Sustained release dosage forms for a jak1 inhibitor
WO2015072580A1 (ja) * 2013-11-14 2015-05-21 学校法人同志社 細胞増殖促進または細胞障害抑制による角膜内皮治療薬
US9498467B2 (en) 2014-05-30 2016-11-22 Incyte Corporation Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1
KR101778004B1 (ko) * 2015-06-22 2017-09-15 (주) 에빅스젠 이마티닙을 유효성분으로 포함하는 안구 건조 질환 예방 및 치료용 약학 조성물
US11154543B2 (en) 2015-10-15 2021-10-26 The Schepens Eye Research Institute, Inc. P38 MAP kinase inhibitors for wound healing
CN105496955A (zh) * 2015-12-11 2016-04-20 北京蓝丹医药科技有限公司 一种二氟泼尼酯眼用乳剂及其制备方法
JPWO2017110093A1 (ja) 2015-12-24 2018-10-11 学校法人同志社 ＴＧＦ−βシグナルに起因する障害を治療または予防するための医薬およびその応用
AR113922A1 (es) 2017-12-08 2020-07-01 Incyte Corp Terapia de combinación de dosis baja para el tratamiento de neoplasias mieloproliferativas
EA202091830A1 (ru) 2018-01-30 2020-12-29 Инсайт Корпорейшн Способы и промежуточные соединения для получения ингибитора jak
MD3773593T2 (ro) 2018-03-30 2024-10-31 Incyte Corp Tratament hidradenitei supurative utilizând inhibitori ai JAK
CA3150975A1 (en) 2019-06-10 2020-12-17 Incyte Corporation Topical treatment of vitiligo by a jak inhibitor
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms
CA3248857A1 (en) * 2022-02-01 2023-08-10 Baylor College Of Medicine RXR AGONISTS IN EYE DISORDERS

Family Cites Families (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4131651A (en) 1977-10-25 1978-12-26 Barnes-Hind Pharmaceuticals, Inc. Treatment of dry eye
US4409205A (en) 1979-03-05 1983-10-11 Cooper Laboratories, Inc. Ophthalmic solution
US4370325A (en) 1979-03-30 1983-01-25 Dermik Laboratories Pharmaceutical compositions and method of treatment
US4753945A (en) 1986-02-19 1988-06-28 Eye Research Institute Of Retina Foundation Stimulation of tear secretion with phosphodiesterase inhibitors
US4883658A (en) 1986-04-28 1989-11-28 Holly Frank J Ophthalmic solution for treatment of dry-eye syndrome
US4744980A (en) 1986-04-28 1988-05-17 Holly Frank J Ophthalmic solution for treatment of dry eye syndrome
US4818537A (en) 1986-10-21 1989-04-04 Liposome Technology, Inc. Liposome composition for treating dry eye
US4966773A (en) 1986-11-25 1990-10-30 Alcon Laboratories, Inc. Topical ophthalmic compositions containing microfine retinoid particles
US5278151A (en) 1987-04-02 1994-01-11 Ocular Research Of Boston, Inc. Dry eye treatment solution
US4914088A (en) 1987-04-02 1990-04-03 Thomas Glonek Dry eye treatment solution and method
US5075104A (en) 1989-03-31 1991-12-24 Alcon Laboratories, Inc. Ophthalmic carboxy vinyl polymer gel for dry eye syndrome
US5174988A (en) 1989-07-27 1992-12-29 Scientific Development & Research, Inc. Phospholipid delivery system
US5041434A (en) 1991-08-17 1991-08-20 Virginia Lubkin Drugs for topical application of sex steroids in the treatment of dry eye syndrome, and methods of preparation and application
DE69115990T2 (de) 1990-05-29 1996-05-30 Ocular Res Of Bonton Inc Zusammensetzung zur Behandlung von Dry Eye Erkrankungen
ZA912797B (en) 1990-05-29 1992-12-30 Boston Ocular Res Dry eye treatment process and solution
ZA927277B (en) 1991-10-02 1993-05-19 Boston Ocular Res Dry eye treatment process and solution.
US5290572A (en) 1992-08-06 1994-03-01 Deo Corporation Opthalmic composition for treating dry eye
ES2176252T3 (es) 1993-07-02 2002-12-01 Altana Pharma Ag Benzamidas sustituidas con fluoro-alcoxi y su utilizacion como agentes inhibidores de fosfodiesterasas de nucleotidos ciclicos.
US6083903A (en) 1994-10-28 2000-07-04 Leukosite, Inc. Boronic ester and acid compounds, synthesis and uses
US5696166A (en) 1995-10-31 1997-12-09 Yanni; John M. Compositions containing hydroxyeicosatetraenoic acid derivatives and methods of use in treating dry eye disorders
WO1997020578A1 (en) * 1995-12-04 1997-06-12 University Of Miami Non-preserved topical corticosteroid for treatment of dry eye, filamentary keratitis, and delayed tear clearance
US5958671A (en) 1996-04-23 1999-09-28 Presidents And Fellows Of Harvard College Methods and compositions for regulating T cell subsets by modulating transcription factor activity
JPH1036289A (ja) 1996-07-24 1998-02-10 Sumitomo Pharmaceut Co Ltd 神経細胞の変性または死滅抑制剤
US5800807A (en) 1997-01-29 1998-09-01 Bausch & Lomb Incorporated Ophthalmic compositions including glycerin and propylene glycol
US6043083A (en) * 1997-04-28 2000-03-28 Davis; Roger J. Inhibitors of the JNK signal transduction pathway and methods of use
JPH10330257A (ja) 1997-06-02 1998-12-15 Senju Pharmaceut Co Ltd 眼局所用サイトカイン産生抑制剤
US5980929A (en) * 1998-03-13 1999-11-09 Johns Hopkins University, School Of Medicine Use of a protein tyrosine kinase pathway inhibitor in the treatment of retinal ischmemia or ocular inflammation
ES2136581B1 (es) 1998-05-27 2000-09-16 Uriach & Cia Sa J Uso de derivados del acido-2-hidroxi-4-trifluorometilbenzoico para la preparacion de medicamentos utiles para inhibir el factor de transcripcion nuclear nf-kb.
WO2000003705A1 (en) * 1998-07-14 2000-01-27 Alcon Laboratories, Inc. Use of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for the manufacture of a medicament for treating non-allergic ophthalmic inflammatory disorders and for the prevention of ocular neovascularization
AU6476599A (en) 1998-11-03 2000-05-22 Novartis Ag Anti-inflammatory 4-phenyl-5-pyrimidinyl-imidazoles
US6458854B2 (en) 1999-11-09 2002-10-01 Alcon Universal Ltd. Phospholipids of hydroxyeicosatetraenoic acid-like derivatives and methods of use
MXPA02004702A (es) 1999-11-09 2004-09-10 Alcon Inc Analogos interrumpidos por heteroatomos de acido 15-hidroxieicosatetraenoico y metodos de uso.
CA2386333A1 (en) 1999-11-09 2001-05-17 Alcon, Inc. 3-heteroatom substituted and two carbon homologs 15-hete and methods of use
US6353032B1 (en) 1999-11-09 2002-03-05 Alcon Universal Ltd. Phospholipids of hydroxyeicosatetraenoic acid-like derivatives and methods of use
US6320062B1 (en) 1999-11-09 2001-11-20 Alcon Universal Ltd. 15-hydroxyeicosatetraenoic acid analogs with enhanced metabolic stability and methods of their use in treating dry eye disorders
AU1101301A (en) 1999-11-09 2001-06-06 Alcon Universal Limited 2,2-difluoro 15-hydroxyeicosatetraenoic acid analogs and methods of use
PL356127A1 (en) 1999-11-09 2004-06-14 Alcon Inc. Omega chain modified 15-hydroxyeicosatetraenoic acid derivatives and methods of their use for the treatment of dry eye
EP1228026B1 (en) 1999-11-09 2004-01-02 Alcon Inc. 15-hydroxyeicosatetraenoic acid-related compounds and methods of use
EP1228030B1 (en) 1999-11-09 2005-06-01 Alcon Inc. Benzenoid derivatives of 15-hydroxyeicosatetraenoic acid and methods of their use in treating dry eye disorders
CA2388044A1 (en) 1999-11-09 2001-05-17 Alcon, Inc. Hydroxyeicosatetraenoate salts, compositions and methods of use in treating dry eye disorders
US6552084B2 (en) 1999-11-09 2003-04-22 Alcon Universal Ltd. Hydroxyeicosatetraenoic acid analogs and methods of their use in treating dry eye disorders
MXPA02004703A (es) 1999-11-09 2004-09-10 Alcon Inc Composiciones que contienen derivados de acido hidroxieicostetraenoico y metodos de uso para tratar trastornos de resequedad en los ojos.
DE60039783D1 (de) 1999-12-14 2008-09-18 Genentech Inc Lfa-1 antagonisten und tnf-alpha antagonisten zur
AU2001288271A1 (en) * 2000-08-17 2002-02-25 Harrihar A. Pershadsingh Methods for treating inflammatory diseases
US20020151491A1 (en) 2000-11-28 2002-10-17 Jian-Dong Li Composition and method for treating the over-production of mucin in diseases such as otitis media using an inhibitor of MUC5AC
US20020132823A1 (en) * 2001-01-17 2002-09-19 Jiahuai Han Assay method
GB0108770D0 (en) * 2001-04-06 2001-05-30 Eisai London Res Lab Ltd Inhibitors
DE60213230T2 (de) * 2001-05-21 2006-11-23 Alcon Inc. Verwendung von NF-Kappa.B Inhibitoren zur Behandlung von Augentrockenheit
ME00565A (en) 2002-05-28 2011-12-20 Topically applicable pharmaceutical preparation
CA2497977A1 (en) * 2002-09-20 2004-04-01 Alcon, Inc. Use of cytokine synthesis inhibitors for the treatment of dry eye disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004026406A1 *

Also Published As

Publication number Publication date
PL374700A1 (pl) 2005-10-31
CA2497977A1 (en) 2004-04-01
US20060189541A1 (en) 2006-08-24
AR041262A1 (es) 2005-05-11
WO2004026406A1 (en) 2004-04-01
KR20050057175A (ko) 2005-06-16
ZA200502119B (en) 2006-09-27
US7026296B2 (en) 2006-04-11
US20040058875A1 (en) 2004-03-25
BR0314603A (pt) 2005-07-26
TW200404534A (en) 2004-04-01
CN1684738A (zh) 2005-10-19
JP2006502183A (ja) 2006-01-19
MXPA05003063A (es) 2005-05-27
AU2003278727A1 (en) 2004-04-08

Similar Documents

Publication Publication Date Title
US7026296B2 (en) Methods of treating dry eye disorders
US6872382B1 (en) Use of selective PDE IV inhibitors to treat dry eye disorders
US6740674B2 (en) Use of proteasome inhibitors to treat dry eye disorders
WO2009052140A1 (en) Use of tnf receptor antagonists for treating dry eye
AU2002308760A1 (en) Use of proteasome inhibitors to treat dry eye disorders
US6645994B1 (en) Method of treating dry eye disorders
EP1393277B1 (en) USE OF NF-Kappa-B INHIBITORS TO TREAT DRY EYE DISORDERS
AU2002309963A1 (en) Use of NF-KAPPA-B inhibitors to treat dry eye disorders
US7235556B2 (en) Methods of treating dry eye disorders
US20030008853A1 (en) Method for treating dry eye disorders
JPS5929616A (ja) 抗炎症眼科用液剤およびその製法
US7223737B1 (en) Method of treating dry eye disorders using glycosides
US7112588B2 (en) Use of proteasome inhibitors to treat dry eye disorders
AU2002316133A1 (en) Method of treating dry eye disorders

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20050223

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ALCON, INC.

17Q First examination report despatched

Effective date: 20070621

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090303